Uncoupling of VEGF with NO as a mechanism for diabetic nephropathy.
VEGF plays protective roles on a variety of non-diabetic renal diseases. However, in diabetes VEGF exhibits deleterious roles to mediate the development/progression of diabetic nephropathy in spite of high VEGF. The protective role of VEGF could be predominantly dependent on its ability to stimulate nitric oxide production in endothelial cell in non-diabetic renal disease. However, it has been known that nitric oxide bioavailability is reduced in diabetes, indicating that diabetic status does not allow high VEGF to lead to an increase in NO bioavailability. As a result, VEGF could engage to NO-independent pathway, and cause deleterious effects on vascular system. Thus, we have hypothesized that uncoupling of VEGF with endothelial NO can be a mechanism by which VEGF causes diabetic nephropathy. We found that diabetic eNOS knockout (KO) mice exhibit masangiolysis, glomerular capillary microaneurysm, Kimmelstiel-Wilson-like nodular lesions, abnormal angiogenesis and a marked macrophage infiltration in addition to mesangial expansion and thickening of GBM, all of that resemble human diabetic nephropathy. Interestingly these lesions were associated with an increase in renal VEGF expression, suggesting uncoupling of VEGF with endothelial NO could be a mechanism. Compatibly, our in vitro experiments demonstrated that VEGF-induced endothelial cell proliferation was enhanced by NO blocking (with LNAME) and suppressed by exogenous NO administration whereas macrophage migration in response to VEGF was inhibited by exogenous NO, suggesting that uncoupling condition could cause abnormal angiogenesis and macrophage infiltration.
Nakagawa
Takahiko
T
Division of Nephrology, Hypertension and Transplantation, University of Florida, PO Box 100224, Gainesville, FL 32610-0224, USA. nakagt@medicine.ufl.edu
D000818:Animals; D003928:Diabetic Nephropathies / Q000209:etiology*; D042783:Endothelial Cells / Q000473:pathology; D006801:Humans; D009389:Neovascularization, Pathologic; D009569:Nitric Oxide / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D042461:Vascular Endothelial Growth Factor A; D009569:Nitric Oxide